The introduction of HIV antiretroviral medication (ARVs) in Africa has resulted in substantial reductions in morbidity and mortality. This project is studying the impact of ARVs on community level incidence in the Rakai Community Cohort Study (RCCS) in Uganda, the impact of ARVs on HIV transmission among HIV discordant couples, impact of immunologic monitoring, and potential delays in detecting virologic failure on transmitted and acquired genotypic ARV resistance. We have shown complete elimination of transmission among discordant couples on ARVs and continue to scale up treatment. We have continued to monitor the impact of combination prevention among high risk fishing communities bordering Lake Victoria. Average ART coverage among HIV-positive persons increased from 18.6% in 2011 to 67.3% by 2015, while MMC coverage among non-Muslim men increased from 24.3% to 49.2% over the same time period. HIV incidence was 4.0 (95%CI: 2.6-5.7) between 2011 and 2012, falling to 3.3 (95%CI: 2.4-4.5) between 2012 and 2014, and to 2.9 (95%CI: 2.2-3.8) between 2014 and 2015. The aIRR comparing the period 2011-2012 to 2014-2015 was 0.75 (95%CI: 0.47-1.20); the aIRR for men was 0.75 (95%CI: 0.39-1.43) and 0.77 for women (95%CI: 0.38-1.56). Rapid scale-up of combination HIV prevention in high-risk fishing communities on Lake Victoria is feasible, and there is preliminary empirical evidence of the effects of these interventions in decreasing HIV incidence. We also assessed migration patterns using data collected between August 2011 and January 2015 from the RCCS. 29% (n=6718) of participants who migrated over 2 years were significantly more likely to be young and female. HIV prevalence among in-migrants was significantly higher than long-term residents in women (adjPRR=1.45; 95%CI: 1.31-1.60) but not men (adjPRR=1.03; 95%CI: 0.89-1.19), and ART use was lower among in-migrants of both genders (women: adjPRR=0.67, 95%CI: 0.57-0.78; men: adjPRR=0.73, 95%CI: 0.57-0.78). HIV prevalence among in-migrants to fishing communities, particularly in women, was higher than to other communities regardless of source location, and was positively correlated with HIV prevalence in the long-term resident population (p=0.002). HIV-infected migrants, largely women, are less likely to use ART and differentially move into hotspot fishing communities. However, migrants from these hotspots do not account for a substantial proportion of migrant-associated HIV infection elsewhere suggesting that test and treat targeted to hotspots may not abate the generalized epidemic. One concern with increased use of ARVs in sub-Saharan Africa is the extent by which viral resistance will develop over time among the non-clade B HIV-1-infected individuals. We measured the levels of transmitted antiretroviral drug resistance among 75 recently infected RCCS seroconverters with documented seroconversion between 2012 and 2013. We found low rates of transmitted antiretroviral drug resistance with only 3 individuals (4%) having resistance, 2 to NNRTIs, one had PI resistance and no resistance found to NRTIs. Viral load monitoring (VLM) to identify individuals failing ART is not widely available in resource-limited settings; most programs use clinical or immunological monitoring (IM) only.. We observed late switching to second line therapy to be a problem among 3,287 HIV-infected persons who initiated ART between 2004 and 2011, of whom 173 met the criteria for virologic failure 6 or more months after ART initiation. 121 (70%) switched to second line ART. The median timing of switching to second line ART was 7.8 months after virologic failure (IQR=3.3-15.2). Cumulative incidences of switching at 6, 12 and 24 months after virologic failure were 33.2% (95% CI=26.2 41.0), 49.8% (95% CI=42.3 57.9) and 71.9% (95% CI=64.2 79.2) respectively. Adjusted mortality was significantly higher in patients not switched to second line ART at 11.1% compared to those switched at 1.6% (p-value==0.005). Among those switched, the longer the time interval between virologic failure and regimen switch, the more patients experienced CD4 decrease and/or further increase in VL during that interval. Herpes simplex virus type 2 (HSV-2) has been shown to up-regulate HIV-1 replication at the cellular level. Our study of Acyclovir suppressive therapy among HIV-1/HSV-2 co-infected patients showed an overall reduction in HIV-1 disease progression by 25% compared to placebo (p=0.04). In a sub-analysis stratified by baseline VL, participants with baseline HIV VL > 50 000 copies/ml treated with Acyclovir had a 38% reduced rate of disease progression compared to placebo (p=0.03). In a secondary analysis, we found that the rate of GUD and HSV-2 shedding doubled in the first 3 months after ARV initiation, returning to baseline by 6 months suggesting a possible IRIS effect. We found a similar increase among these same women when we measured vaginal CMV shedding. We assessed the humoral immune response to CMV among women in this trial to investigate any association with disease progression and immune activation. We found that the highest CMV IgG tertile at baseline was independently associated with the primary outcome (ART initiation or death) compared to the lowest CMV IgG tertile (adjusted Hazard Ratio=1.59 95%CI=1.05-2.39; P=0.027). Among pre-ART visits, log10 CMV IgG antibody levels were positively associated with soluble CD14 and log10 C-reactive protein levels (P<0.01). The humoral immune response to CMV was associated with HIV disease progression and immune activation. Optimizing the HIV care cascade is a critical component to achieving an AIDS free generation globally. To evaluate strategies to improve engagement in HIV case and prevention, 442 ART-nave, HIV-infected adult participants were randomized to peer support or standard of care.. After a median follow-up of 363 days, intervention participants were more likely to report being in care (92% vs. 84%; p=0.018), on cotrimoxazole (89% vs. 81%; p=0.022), and adherent to safe water vessel use (23% vs. 14%; p=0.022). The intervention effect was observed primarily among participants not in care at baseline (n=139) with 83% vs. 53% (p=0.003) of these intervention participants in care at follow-up compared to controls, 78% vs. 58% on cotrimoxazole (p=0.02), and 20% vs. 4% adherent to safe water vessel use (p=0.017). We also evaluated the impact of patient-selected care buddies on HIV adherence to care, disease progression and conduct of daily life among pre-antiretroviral HIV-infected patients in a randomized controlled trial in Rakai. This study found that in pre-ART HIV-infected persons, having care buddies improved the conduct of daily life, but had limited effect on HIV disease progression and CD4 monitoring adherence. Understanding the extent to which HIV burden differs across communities and the drivers of local disparities is critical for an effective and targeted HIV response. To determine variability in HIV rates we measured HIV prevalence among 17,119 individuals (54% female) from the Rakai cohort. There was large variation in HIV prevalence, ranging from 9% to 43% across communities. Fishing communities had a higher median HIV prevalence (41%, range: 37-43%) compared to trading (17%, range: 11-22%) and agrarian communities (14%, range: 9-26%); ART and male circumcision coverage were significantly lower in fishing communities. Self-reported risk behaviors were significantly higher in men compared to women and in fishing communities compared to other community types. There is substantial heterogeneity in HIV prevalence, risk factors, and service uptake across communities. These findings underscore the need for local surveillance and have important implications for the design of targeted HIV responses.